Decreased IL-10 accelerates B-cell leukemia/lymphoma in a mouse model of pediatric lymphoid leukemia

Exposures to a wide repertoire of common childhood infections and strong inflammatory responses to those infections are associated with risk of pediatric B-cell acute lymphoblastic leukemia (B-ALL) in opposing directions. Neonatal inflammatory markers are also related to risk by unknown mechanism(s). Here, we demonstrate that IL-10 deficiency, which is associated with childhood B-ALL, indirectly impairs B lymphopoiesis and increases B-cell DNA damage in association with a module of 6 proinflammatory/myeloid-associated cytokines (IL-1α, IL-6, IL-12p40, IL-13, MIP-1β/CCL4, and G-CSF). Importantly, antibiotics attenuated inflammation and B-cell defects in preleukemic Cdkn2a-/-Il10-/- mice. In an ETV6-RUNX1+ (E6R1+) Cdkn2a-/- mouse model of B-ALL, decreased levels of IL-10 accelerated B cell neoplasms in a dose dependent manner, and altered the mutational profile of these neoplasms. Our results illuminate a mechanism through which a low level of IL-10 can create risk of leukemic transformation and support developing evidence that microbial dysbiosis contributes to pediatric B-ALL.

The Neurotensinergic System: A Target for Cancer Treatment

Background: The scientific interest regarding the involvement of peptides in cancer has increased in the last years. In tumor cells the overexpression of peptides and their receptors is known and new therapeutic targets for the treatment of cancer have been suggested. The overexpression of the neurotensinergic system has been associated with poor prognosis, tumor size, higher tumor aggressiveness, increased relapse risk and worse sensitivity to chemotherapy agents. Objective: The aim of this review is to update the findings regarding the involvement of the neurotensinergic system in cancer to suggest anticancer therapeutic strategies targeting this system. The neurotensin (NT) precursor, NT and its receptors (NTR) and the involvement of the neurotensinergic system in lung, breast, prostate, gastric, colon, liver and pancreatic cancers, glioblastoma, neuroendocrine tumors and B-cell leukemia will be mentioned and discussed as well as the signaling pathways mediated by NT. Some research lines to be developed in the future will be suggested such as: molecules regulating the expression of the NT precursor, influence of the diet in the development of tumors, molecules and signaling pathways activated by NT and antitumor therapeutic strategies targeting the neurotensinergic system. Conclusion: NT, via the NTR, exerts oncogenic (tumor cell proliferation, invasion, migration, angiogenesis) and antiapoptotic effects, whereas NTR antagonists inhibit these effects. NTR expression can be used as a diagnostic tool/therapeutic target and the administration of NTR antagonists as antitumor drugs could be a therapeutic strategy to treat tumors overexpressing NTR.

Differential expression of pre-B-cell leukemia homeobox 1 in human epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published and public microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding pre-B-cell leukemia homeobox 1, PBX1, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. PBX1 expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. PBX1 expression correlated with progression-free survival in patients with p53 mutant ovarian cancer. These data indicate that expression of PBX1 is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. PBX1 may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

Leptin and TGF-β1 Downregulate PREP1 Expression in Human Adipose-Derived Mesenchymal Stem Cells and Mature Adipocytes

Adipose tissue is widely recognized as an extremely active endocrine organ producing adipokines as leptin that bridge metabolism and the immune system. Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (PREP1) is a ubiquitous homeodomain transcription factor involved in the adipogenic differentiation and insulin-sensitivity processes. Leptin, as pleiotropic adipokine, and TGF-β, known to be expressed by primary pre-adipocytes [adipose-derived stem cells (ASCs)] and mature differentiated adipocytes, modulate inflammatory responses. We aimed to assess for the first time if leptin and TGF-β interfere with PREP1 expression in both ASCs and mature differentiated adipocytes. Human ASCs were isolated from subcutaneous adipose liposuction and, after expansion, fully differentiated to mature adipocytes. In both ASCs and adipocytes, leptin and TGF-β1 significantly decreased the expression of PREP1, alone and following concurrent Toll-like receptor 4 (TLR4) activation. Moreover, in adipocytes, but not in ASCs, leptin increased TLR4 and IL-33 expression, whereas TGF-β1 enhanced TLR4 and IL-6 expression. Taken together, we provide evidence for a direct regulation of PREP1 by leptin and TGF-β1 in ASCs and mature adipocytes. The effects of leptin and TGF-β1 on immune receptors and cytokines, however, are limited to mature adipocytes, suggesting that modulating immune responses depends on the differentiation of ASCs. Further studies are needed to fully understand the regulation of PREP1 expression and its potential for the development of new therapeutic approaches in obesity-related diseases.

Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance)

Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age <70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124.

Novel Markers in Pediatric Acute Lymphoid Leukemia: The Role of ADAM6 in B Cell Leukemia

BackgroundThe extensive genetic heterogeneity found in the B cell precursor acute lymphoblastic leukemia (BCP-ALL) subtype of childhood ALL represents a potential repository of biomarkers. To explore this potential, we have carried out in silico analysis of publicly available ALL datasets to identify genetic biomarkers for childhood BCP-ALL, which could be used either individually or in combination as markers for early detection, risk stratification, and prognosis.MethodsTo explore novel genes that show promising clinical and molecular signatures, we examined the cBioPortal online tool for publicly available datasets on lymphoid cancers. Three studies on lymphoblastic and lymphoid leukemia with 1706 patients and 2144 samples of which were identified. Only B-Lymphoblastic Leukemia/Lymphoma samples (n = 1978) were selected for further analysis. Chromosomal changes were assessed to determine novel genomic loci to analyze clinical and molecular profiles for the leukemia of lymphoid origin using cBioPortal tool.ResultsADAM6 gene homozygous deletions (HOM:DEL) were present in 59.60% of the profiled patients and were associated with poor ten years of overall patients’ survival. Moreover, patients with ADAM6 HOM:DEL showed a distinguished clinical and molecular profile with higher Central Nervous System (CNS) sites of relapse. In addition, ADAM6 HOM:DEL was significantly associated with unique microRNAs gene expression patterns.ConclusionADAM6 has the potential to be a novel biomarker for the development and progress of BCP- ALL.

Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts

Chimeric antigen receptor T-cells (CAR T-cells) for the treatment of relapsing/refractory B-cell precursor acute lymphoblastic leukemia have led to exciting clinical results. However, CAR T-cell approaches revealed a potential risk of CD19-/CAR+ leukemic relapse due to inadvertent transduction of leukemia cells.BackgroundMethodsWe evaluated the impact of a high percentage of leukemia blast contamination in patient-derived starting material (SM) on CAR T-cell drug product (DP) manufacturing. In vitro as well as in vivo models were employed to identify characteristics of the construct associated with better profile of safety in case of inadvertent B-cell leukemia transduction during CAR T-cell manufacturing.ResultsThe presence of large amounts of CD19+ cells in SM did not affect the transduction level of DPs, as well as the CAR T-cell rate of expansion at the end of standard production of 14 days. DPs were deeply characterized by flow cytometry and molecular biology for Ig-rearrangements, showing that the level of B-cell contamination in DPs did not correlate with the percentage of CD19+ cells in SM, in the studied patient cohort. Moreover, we investigated whether CAR design may affect the control of CAR+ leukemia cells. We provided evidences that CAR.CD19 short linker (SL) prevents complete epitope masking in CD19+CAR+ leukemia cells and we demonstrated in vitro and in vivo that CD19 +CAR(SL)+leukemic cells are killed by CAR.CD19 T-cells.ConclusionsTaken together, these data suggest that a VL-VH SL may result in a safe CAR-T product, even when manufacturing starts from biological materials characterized by heavy contamination of leukemia blasts.

A new pathological classification of intrahepatic cholangiocarcinoma according to protein expression of SSTR2 and Bcl2

Background No universal classification method for intrahepatic cholangiocarcinoma (IHCC) has been reported based on the embryological origin of biliary epithelial cells. The aim of this study was to classify IHCC according to protein expression levels of somatostatin receptor 2 (SSTR2) and b-cell leukemia/lymphoma 2 (Bcl2) and to elucidate the clinicopathological features of each group. Methods Fifty-two IHCC patients who underwent hepatic resection were enrolled in this study. Protein expression levels of SSTR2 and Bcl2 were examined using immunohistochemistry. Clinicopathological factors were compared between the three groups and prognostic factors were investigated. Results The patients were divided into three groups: SSTR2 positive and Bcl2 negative (p-Group H, n = 21), SSTR2 negative and Bcl2 positive (p-Group P, n = 14), and the indeterminate group (p-Group U, n = 17) for cases where SSTR2 and Bcl2 were both positive or both negative. All p-Group P cases displayed curability A or B. The 5-year survival rates of p-Group H and U patients were worse than those in p-Group P. p-Group H had higher T-factor, clinical stage, and incidence of periductal infiltration than p-Group P. Conclusions This method could be used to classify IHCC into peripheral and perihilar type by embryological expression patterns of SSTR2 and Bcl2.